The major barriers to preventing or treating Alzheimer's disease (AD) are its unknown pathogenesis/etiology and the lack of an objective, sensitive and specific biomarker of the disease, particularly at the early stages when therapeutic interventions would likely have the greatest efficacy. The basic hypothesis of this proposal is that levels of a novel protein-protein complex present in cerebrospinal fluid (CSF) are able to differentiate AD subjects from age-matched controls and subjects with non-AD neurologic disorders. In addition, the biomarker complex appears to identify subjects with mild cognitive impairment (MCI), the earliest clinical manifestation of AD. Analysis of lumbar CSF from a small number of living probable AD and age-matched controls showed 100% sensitivity and 93% specificity in the identification of AD subjects. The proposed studies will enhance our understanding of the way in which the protein complex is generated and will further validate our initial findings by: 1) using Western blot analysis, sequential immunoprecipitation and mass spectrometry to examine individual components of the protein complex in ventricular CSF from MCI, LAD and age-matched control subjects; and 2) to quantify levels of the protein complex in small volumes of unprocessed CSF from autopsied MCI, LAD and age-matched controls and lumbar CSF from living, probable AD and age- matched controls using an enzyme linked immunoassay developed in our laboratory that is based on trapping one component of the complex and quantifying the other component. Together these studies will provide further validation of our preliminary findings and will provide support for wide scale testing of the protein-protein complex as an objective biomarker of AD and MCI. Alzheimer's disease (AD) is the fourth leading cause of death in the United States and currently affects 4.5 million Americans. Two major barriers to treating and eventually preventing AD are: 1) the lack of understanding about the process of neuron degeneration and loss and 2) the lack of a sensitive and specific biomarker of the disease. Preliminary and future studies described in this proposal show that a novel protein-protein complex present in cerebrospinal fluid can be quantified using an enzyme linked immunoassay (ELISA). This protein-protein complex is a sensitive and specific biomarker of AD including early stages of AD (mild cognitive impairment) when therapeutic interventions are most likely to have beneficial effects. [unreadable] [unreadable] [unreadable]